1. Field of the Invention
The present invention relates generally to medical apparatus, systems, methods, and kits. More particularly, the present invention relates to methods and apparatus for isolating sub-bronchial regions of the lung and delivering or retrieving substances from such isolated regions.
Lung access and isolation is of interest in numerous therapeutic and diagnostic medical procedures. In particular, access to the lungs is useful for both local and systemic drug delivery, lung lavage, visual assessment and diagnosis of lung function, and the like.
For drug delivery, access is most simply achieved by introducing an aerosol to the lungs through the mouth or nose, and a variety of inhalers, nebulizers, metered dose inhalers (MDIs), nasal sprayers, and the like, have been developed over the years. While very effective for many drugs, delivery through the mouth or nose can be very inefficient, often with less than 20% of the drug reaching circulation or a targeted local treatment region. Moreover, inhalation through the mouth or nose is not able to target drug delivery to a particular region of the lungs. While this may not be a problem for systemic delivery, it can be a significant drawback in the treatment of localized disease where a highly controlled delivery profile would be preferred.
In an effort to overcome at least some of these shortcomings, a variety of endotracheal drug delivery and lung lavage systems have been developed. Most simply, an endotracheal or tracheostomy tube having an inflatable cuff at its distal end may be placed in a patient""s trachea and used to deliver a drug aerosol to the whole of the lungs. While this can improve the efficiency of drug delivery (reducing the amount of drug deposited in the nasal passages or throat), it helps little in targeting treatment within any particular region of the lungs. Thus, it has been further proposed to use a secondary catheter placed through an endotracheal or tracheostomy tube for selectively isolating the left or right bronchus. For example, the secondary catheter can have an inflatable cuff which is positioned immediately beyond the main branching between the left and right bronchi. One of the bronchi can then be accessed through the secondary catheter while the other is accessed through the tracheal tube. Such systems are described, for example, in U.S. Pat. Nos. 5,285,778 and 5,660,175. While such systems offer significant benefits over the use of an endotracheal tube by itself, they still do not permit isolation of sub-bronchial regions of the lung for drug delivery, lavage, or any other purpose.
A system for bronchoalveolar lavage which can isolate a sub-bronchial region of the lung is described in published Application No. WO 92/10971. A co-axial catheter system is placed through an endotracheal tube, with the inner most catheter having an isolation wedge or balloon which can be positioned in a remote bronchiole to effect isolation of a distal region of the lung. The outer catheter has no capability for isolating the lung and is used, for example, for ventilating the lung proximal to the isolation cuff. While potentially an improvement over prior systems, the apparatus of WO 92/10971 will be very difficult to position, making targeting of particular sub-bronchial regions very difficult. Moreover, the inability to isolate a bronchus upstream from the distal isolation cuff limits the ability to selectively treat different regions of the bronchus in different ways. That is, while the particular sub-bronchial region which is isolated by the distal isolation cuff may be treated in one way, the remainder of that bronchus as well as the entire other lung must be ventilated and treated in a common manner through either the endotracheal tube or the outer catheter of the co-axial catheter pair.
For these reasons, it would be desirable to provide improved apparatus, systems, methods, and kits for the treatment and diagnosis of selected regions of a patient""s lungs, particularly a lobar or targeted sub-lobar regions of the patient""s lungs. The present invention should provide for the efficient delivery of pharmaceutical and other substances to the targeted sub-lobar regions of the lung. Moreover, in some embodiments, the present invention should be able to provide at least a second level of isolation within a particular bronchus and/or the ability to instill the pharmaceuticals or other substances at a point significantly distal to a point of isolation within the bronchus. The systems and apparatus of the present invention should be capable of being positioned precisely to a targeted bronchi within the bronchus, preferably providing on-board visualization while components of the system are positioned over a guidewire. Additionally, the apparatus, systems, methods, and kits of the present invention should be suitable for a wide variety of purposes, including pharmaceutical drug delivery, lung lavage (optionally in combination with drug delivery), diagnosis (optionally in combination with lung lavage), and the like. In particular, the present invention should be useful for localized drug delivery where a particular drug or other therapeutic agent can be delivered to a well-defined, isolated sub-bronchial region of the lung (as defined hereinafter) with little or no delivery to other regions of the lung. At least some of these objectives will be met by the inventions described hereinafter.
2. Description of the Background Art
WO 92/10971 describes a bronchoalveolar lavage catheter system having an outer catheter and an inner catheter with an enlarged (optionally inflatable) tip which is advanced until the tip wedges in a bronchiole of the patient. A region of the lungs distal to the enlarged tip may then be lavaged to retrieve sample. U.S. Pat. Nos. 5,660,175; 5,653,231; 4,716,896; and 4,453,545, describe single and co-axial catheter systems for accessing a patient""s lungs. U.S. Pat. No. 5,285,778, describes a co-axial endoscopic lung access system. U.S. Pat. Nos. 5,309,903 and 5,207,220 describe systems for administering liquid pharmaceutical formulations to an isolated lung.
The present invention provides improved apparatus, systems, methods, and kits for isolating lobar and sub-lobar regions of a patient""s lungs. The isolated region will be a portion (not the whole) of the right or left lung, and isolation will be accomplished by occluding a bronchial passage at at least one location in the lobar, segmental, and subsegmental bronchus. Thus, a primary occlusion will be formed after both the main bifurcation of the trachea and a further bifurcation into the lobar bronchus. Optionally, the lobar and/or sub-lobar region can be further isolated at at least one secondary location distal to the primary point of isolation and usually after further branching of the bronchial passages. Isolation at the primary location and optional additional locations within the bronchial passages will usually be effected by expansion of an occlusion member, such as an inflatable cuff, inflatable balloon, or the like.
Once the lobar or sub-lobar region has been isolated, a variety of therapeutic and diagnostic procedures can be performed within the isolated region. For example, pharmaceutical formulations including small molecule drugs, biological macromolecular drugs, and the like, can be specifically delivered to the isolated region with minimal or no cross-delivery to other regions of the lungs. Similarly, lavage may be performed within the isolated region with minimal impact on adjacent regions of the lungs. Isolation of the lobar or sub-lobar region permits such drug delivery and lavage procedures to be further controlled by control of the volumes, rates, pressures, temperatures, repetitions, retention times, and other method and system parameters. For example, the pressure within the isolated region can be controlled separately from the pressure or pressures maintained outside of the isolated region. In this way, a variety of delivery parameters can be controlled. By elevating pressure within the isolated region above that in the surrounding regions of the lung, the isolated lobar or sub-lobar region will be expanded which may, in some cases, enhance delivery of a drug or permit more efficient lavage of the region. Alternatively, by elevating pressure within the xe2x80x9cotherxe2x80x9dlung regions above that within the isolated region, the risk of migration of toxic therapeutic or other agents away from the isolated region can be greatly reduced.
According to the present invention, an isolation catheter comprises a catheter body having a proximal end, a distal end, and a main lumen therebetween. An expansible occlusion member is disposed at or near the distal end of the catheter body, and optical and illumination fibers are disposed in the catheter body to permit imaging of a region distal to the distal end of the catheter body when the catheter is in use. Usually, a hub will be attached to the proximal end of the catheter and include at least one connection port for the main lumen of the catheter. Optionally, the hub will contain a second connection pert for the optical and illumination fibers, and may contain further connection ports for other lumens and capabilities of the catheter, as described hereinafter.
The catheter body of the isolation catheter will be adapted and sized to allow advancement of the distal end of the catheter body to a target bronchial passage within the lung which is located distal to a first branching of the right or left main stem bronchus. Usually, at least a distal region of the catheter body will have an outer diameter which is sufficiently small and flexible to be advanced into bronchioles having a diameter below about 12 mm, preferably below about 10 mm, and often below about 8 mm. Exemplary catheter bodies will have a length in the range from 40 cm to 150 cm, preferably from 50 cm to 90 cm, an outer diameter in the range from 2 mm to 7 mm, preferably from 3 mm to 6 mm, and a main lumen diameter in the range from 1 mm to 6 mm, preferably from 2 mm to 4 mm. The expansible occlusion member will typically be an inflatable cuff or balloon having an expanded diameter in the range from 4 mm to 18 mm, preferably from 6 mm to 15 mm, and a length in the range from 5 mm to 30 mm, preferably from 10 mm to 15 mm. Usually, the catheter body will include at least one additional lumen for inflation of the inflatable cuff, and the additional lumen will be connected to an additional connector port on the catheter hub. Further optionally, the catheter body may include an additional lumen disposed to direct a washing fluid over a distal tip of the optical fiber which terminates at or near the distal end of the catheter body.
In a preferred aspect, systems according to the present invention comprises an isolation catheter as described above combined with an inner catheter to form a lung infusion/aspiration system. The inner catheter has a proximal end, a distal end, and a central lumen extending between the proximal end and distal end. The inner catheter is positionable within the main lumen of the isolation catheter so that the catheters may be used together in a co-axial fashion and further so that an annular lumen is formed within the main lumen of the isolation catheter, i.e., between an inner surface of the main lumen of the isolation catheter and an outer surface of the inner catheter. Optionally, the connector port on the isolation catheter has an additional connector port for the annular lumen. Alternatively, the system may comprise an adapter connectable to the hub on the isolation catheter, where the adapter has a connector port for the annular lumen. The dimensions and physical characteristics of the inner catheter will be chosen to permit introduction through the main lumen of the isolation catheter and farther to permit advancement of the inner catheter beyond the distal end of the isolation catheter into bronchial passages or bronchioles distal to the isolation catheter when in use.
An exemplary inner catheter has an outer diameter in the range from 0.5 mm to 4.5 mm, preferably from 1.5 mm to 3.5 mm, an inner lumen diameter in the range from 0.1 mm to 3.5 mm, preferably from 1 mm to 3 mm, and a length which is at least 10 cm longer than the isolation catheter in the system. Typically, the inner catheter will have a length in the range from 50 cm to 200 cm, preferably from 60 cm to 110 cm. Optionally, the inner catheter may have an expansible occlusion member disposed near its distal end to permit selective isolation of a lobar or sub-lobar region between proximal and distal points along the bronchial passages of the lung. Typically, the expansible occlusion member on the inner catheter is an inflatable cuff having an expanded diameter in the range from 4 mm to 18 mm, preferably from 6 mm to 15 mm, and a length in the range from 5 mm to 30 mm, preferably from 10 mm to 15 mm.
When including an inflatable cuff, the inner catheter will usually further comprise an inflation lumen disposed to deliver and remove an inflation medium to the inflatable cuff. Moreover, when provided with an inflatable cuff, the inner catheter will usually comprise an infusion/aspiration lumen having a distal port position proximally of the inflatable cuff so that substances, washing fluids, or the like, may be delivered or aspirated through the lumen between the inflatable cuff on the isolation catheter and the inflatable cuff on the inner catheter. Still further optionally, the inner catheter may comprise a vibratory element, such as an ultrasonic transducer, near its distal end to assist in dissolution of occlusive materials, enhance drug uptake, or the like. Still further optionally, the inner catheter may comprise two or more lumens, where at least two of the lumens are joined near a distal end to permit mixing of two or more gas or liquid streams which are being delivered through the catheter. The mixed streams are then released through a common outlet port on the inner catheter. Alternatively, the two streams may be delivered in parallel from the distal tip of the inner catheter for a variety of purposes.
The systems of the present invention may comprise further elements, such as guidewires, tracheal tubes with integral visualization (including both endotracheal and tracheostomy tubes), therapeutic or diagnostic reagents, and/or other system components intended to cooperate in performing the methods of the present invention as described in more detail below. Additionally, the systems of the present invention may be incorporated into kits where one or more system components are packaged together with instructions for use setting forth the methods described in more detail below. Such kits will usually further comprise packages for holding the system component(s) together with the instructions for use.
Methods according to the present invention comprise using an isolation catheter and an inner catheter (generally as described above) for isolating a lobar or sub-lobar region of the lung, and then performing a procedure within the isolated region. In a first instance, the methods are used for delivering a substance, typically a drug or other pharmaceutically active substance, to the isolated region. In a second instance, the methods are used for lavaging the isolated region, i.e., introducing and removing a washing liquid such as isotonic saline, alcohol, mucolytic agents, or the like, to the region. Optionally, the lavage and substance delivery methods can be combined where a drug or other active agent is included in the washing liquid which is being used for lavage. The methods of the present invention comprise positioning a distal end of the isolation catheter within a bronchial passage beyond a first branching within the right or left lung. The inner catheter is then positioned through the main lumen of the isolation catheter so that a distal end of the inner catheter lies in a bronchial passage distally beyond the distal end of the isolation catheter. At least one occlusion element near the distal end of the isolation catheter is expanded within the bronchial passage to isolate a target lobar or sub-lobar region. Thereafter, in the case of drug or other substance delivery, the substance may be delivered through the inner catheter to the isolated region of the lung. In the case of lavage, the washing liquid may be infused through either (or both) of the inner catheter or the isolation catheter and aspirated through the other (or both) of the two catheters. Infusion and aspiration may be performed sequentially or concurrently, or in combinations of both sequential and concurrent infusion and aspiration. Often, it will be preferred to infuse the washing liquid through the inner catheter so that it enters the isolated region generally in a distal portion thereof and diffuses or migrates back toward the isolation catheter where it is collected and removed. In some instances, the washing liquid drug, or other substance may be introduced as a bolus and held or retained within the isolated sub-lobar region for a pre-selected retention time prior to initiating aspiration. In other instances, it may be desirable to continuously both infuse and aspirate the washing liquid drug, or other substance to get a xe2x80x9ccirculationxe2x80x9d of the substance through the isolated lobar or sub-lobar region. Optionally, the washing liquid may comprise a d-rug or other biologically active substance to perform a therapeutic action while the region is being lavaged.
In the case of substance delivery, the substance may comprise any one of a wide variety of pharmaceutical agents, including small molecule drugs, protein drugs, carbohydrate drugs, nucleic acid drugs (genes, optionally in combination with delivery vectors and/or expression control segments), and the like. The delivered substances may be in the form of an aerosol, optionally produced within the inner catheter or prior to introduction to the inner catheter. Still further optionally, the substance may comprise a liquid which is instilled through the inner catheter. For both substance delivery and lavage, it will frequently be preferred to position the isolation catheter and inner catheter through a visualizing endotracheal or tracheostomy tube which has been previously placed in the patient""s trachea. Suitable visualizing endotracheal tubes are described, for example, in U.S. Pat. No. 5,285,778, the full disclosure of which is incorporated herein by reference. Usually, a visualizing endotracheal or tracheostomy tube will include an inflatable cuff or other occlusion element so that the whole lungs may be isolated from the upper regions of the trachea. In this way, the patient may be ventilated through the tracheal tube while other regions of the lung are isolated. Moreover, direct visualization at the bifurcation between the left and right lungs helps position in place the isolation catheter to the target region to be isolated. Additionally, the regions of the lung above or proximal to the occlusion element on the isolation catheter may be ventilated and maintained at a different pressure through the tracheal tube. Thus, by employing isolation cuffs on the tracheal tube, the isolation catheter, and the inner catheter, at least three isolated zones within the lung may be maintained with different pressures being simultaneously maintained. Moreover, different substances can be delivered to each of these regions through the lumens of the inner catheter, isolation catheter, and the tracheal tube, respectively. Often, pressure within the isolated region may be maintained higher than that within the proximal regions of the lung (where pressure is being controlled through the tracheal tube) resulting in expansion of the isolated region which may be beneficial for a variety of reasons. Alternatively, pressure within the isolated region may be maintained below that of the proximal portions of the lung, reducing the risk of release of materials from the isolated region into the proximal portions of the lung. Moreover, when the inner catheter has an isolation cuff, a third distal region of the lung may be pressurized separately from the intermediate and proximal regions.
Introduction of the isolation catheter and/or inner catheter will preferably be performed over a guidewire. The guidewire will first be introduced to a point beyond the location in a bronchial passage where it is desired to position a distal end of the isolation catheter and/or inner catheter. Preferably the isolation catheter will comprise optical and illumination fibers which permit direct visual observation of the guidewire as the guidewire and isolation catheter are advanced. In particular, the guidewire and isolation catheter can be advanced in tandem so that, as successive bifurcations are approached, the physician can steer a curved end of the guidewire into the desired branch bronchial passage. Aft(r positioning the isolation catheter at its desired final location, an occlusion cuff may be expanded and the inner catheter optionally introduced over the guidewire or introduced directly through the main lumen of the isolation catheter without a guidewire. While the inner catheter may in some instances incorporate optical and illumination fibers, it will usually not have such imaging capabilities. Thus, positioning of the inner catheter will frequently be done solely by observation from the isolation catheter and/or under fluoroscopic or other external imaging. Of course, positioning of an isolation catheter can also be performed solely under fluoroscopic imaging (or in combination with both direct visual and fluoroscopic imaging), particularly when the isolation catheter does not include imaging capability.
In a further specific aspect of the methods of the present invention, the inner catheter may be moved and repositioned within the bronchial passages of the isolated region to deliver a substance or release a washing fluid for lavage at different points within the region. Optionally, the inner catheter can be moved (i.e., advanced distally or drawn proximally) while the substance or washing liquid is being released in order to better distribute the material within the isolated region. Further optionally, the inner catheter could also be moved through the isolated region in order to aspirate materials which have been introduced, either alone or in combination with aspiration through the main lumen of the isolation catheter.
Kits according to the present invention include at least an isolation catheter, and optionally include an inner catheter, a tracheal tube, and/or a guidewire. Other components including medical and bioactive reagents, e.g., drugs, washing liquids, or the like, may also be provided within the kits. In addition to the isolation catheter and optional other system components, the kits will comprise instructions for use setting forth a method of the present invention as generally set forth above. The kits will usually be packaged together in conventional medical packaging, such as a pouch, tray, tube, box, bag, or the like. Instructions for use may be provided on a separate printed sheet, or may printed in whole or in part on the packaging materials. When printed separately, the instructions are commonly referred to as a package insert. Usually, at least the isolation catheter and other components of the kit which would be used in the procedure will be packaged in a sterile manner within the kit.